Bone tissue has a remarkable ability to regenerate and thereby repair injuries and other defects. Such repair relies on an equilibrium between an anabolic (osteogenic) and a catabolic (bone resorption) process, i.e. an interplay between bone-forming cells, known as osteoblasts and bone-resorbing cells, known as osteoclasts, whereby bone is continuously being destroyed (resorbed) and rebuilt. Thus, typically under conditions where enhanced bone formation is needed, for example when bone tissue sustains damage such as a fracture, osteoblasts precursor cells proliferate and differentiate toward mature osteoblasts to regenerate bone. However, there are many circumstances, wherein osteoblasts cannot be activated effectively, such as in the case of complex bone fracture or damage, caused by e.g. severe injury, deformity, illness or during a surgical procedure, possibly in combination with osteomyelitis, or in the case of a disturbance in the fine-tuned balance between bone resorption and bone formation as a direct result of a number of diseases.
Treatment of such bone defects have typically been based on bone grafts. Autograft techniques have been known for over 100 years and include the use of cortical and cancellous bone as grafting material. While the use of autografts is preferred due to their low risk of disease transmission, it also presents several serious drawbacks including the limited amount of potential donor material available, the requirement of an additional surgical procedure, as well as size and shape limitations of the bone. Allografts on the other hand may have the benefits of avoiding two-site surgery on the patient, but they have increased risks of disease transmission and immunogenic implant rejection. Thus over the past decades research has focused on obtaining bone graft substitutes that could be used in place of the transplanted bone to stimulate bone healing and provide a strong and biologically compatible framework for new bone to grow into.
These alternatives include for example compositions based on demineralized bone matrix (DBM) (e.g. U.S. Pat. No. 5,481,601), collagen, various calcium phosphates, such as beta-tricalcium phosphate (Ca3(PO4)2) (beta-TCP), alpha-tricalcium phosphate (alpha-TCP) and hydroxyapatite (HA) (e.g. U.S. Pat. No. 4,623,553), and composites thereof, i.e. for example in combination with further osteoinductive materials, such as specific bone growth and differentiation factors, bone morphogenetic proteins (e.g. U.S. Pat. Nos. 7,172,629; 4,394,370; 4,472,840; 4,620,327), bone marrow cells (BMC), and more recently compositions based on platelet-rich plasma (PRP).
PRP is an enriched platelet-containing mixture containing 95% platelets with 4% red blood cells and 1% white blood cells. It is isolated from whole blood and resuspended in a small volume of plasma. Upon combination with activating agents such as thrombin or calcium chloride, the platelets are activated to release their contents such as cytokins and other growth factors. PRP has been used in medicine, primarily in bone grafting and dental implant applications. For example, U.S. Pat. No. 6,322,785 discloses an autologous, thrombin-free platelet gel that includes PRP and collagen (for activation) for craniofacial and joint reconstruction, dental implants as well as bone defects and fractures. In vitro preparation, gelling and subsequent insertion into a mandibular void is described. EP 1 508 311 describes the use of a tube consisting of hydroxyapatite ceramics and optionally having PRP introduced therein for fixing an implant in an alveolar bone or gnathic bone. EP 1 239 894 B1 discloses a bone generating product comprising a coagulated matrix of PRP with thromboplastin in the presence of at least a phospholipid and an effective amount of a calcium containing compound dispersed in the matrix for inducing the formation of bone.
Applications in other areas of medicine include for example PRP as part of a composition for wound healing (U.S. Pat. No. 5,599,558) and tissue repair (U.S. Pat. No. 6,811,777), for use as a tissue sealant (U.S. Pat. No. 5,585,007) or in combination with a biopolymer to temporarily block arteries and veins (U.S. Pat. No. 5,614,204).
To date the use of PRP in bone repair has been designed for treating smaller bone defects such as acquired and congenital craniofacial and other skeletal or dental anomalies (see e.g., Glowacki et al., Lancet 1: 959 (1981)); performing dental and periodontal reconstructions where lost bone replacement or bone augmentation is required such as in a jaw bone; and supplementing alveolar bone loss resulting from periodontal disease to delay or prevent tooth loss (see e.g. Sigurdsson et al., J Periodontol, 66: 511 (1995)). However, such repair appears to be quite different from the induction of bone formation required to fill non-union fractures, segmental gaps or bone voids caused, for example by injury or illness, such as removal of a bone tumor or cyst. These cases require bone grafting or induction of new bone growth employing a different type of matrix or scaffolding to serve as a bone growth substitute.
For such uses, compositions have been developed in form of a non-flowable mass, for example as sheets, puttys or in combination with biopolymers and/or have been crosslinked with e.g. glutaraldehyde, formaldehyde or other chemical crosslinking or subjected to gelling prior to application to a bone defect to provide a preformed scaffold and thereby reducing their flowability and ensuring their retention at the site of bone defect. However, this requires lengthy pre-treatment of the compositions and additions of foreign substances which may have adverse effects in vivo.
Clearly, no osteogenic composition has yet been found to be optimal in generalized usage, and clinical results vary widely even with seemingly well defined compositions. There remains a need for improved osteogenic implant materials that are consistently strongly osteoinductive and osteoconductive, and do not cause any adverse effects in vivo, that are easily accessible and allow ease of handling in surgical procedures, that provide strength and stability for new bone formation during the early stages of bone development, and that are applicable to all sizes of bone defects (ranging from small defects to large gaps). Preferably such compositions are essentially completely incorporated and remodelled into bone by the end of the osteogenic process, thus without need of further surgical procedures. The present invention is addressed to these needs.
Applicants have discovered that the above disadvantages can be overcome by using a biocompatible implant system comprising a PRP gel composition, optionally supplemented with autologous osteogenic factors, nanoparticulate minerals, etc., to induce and promote bone growth within the bone defect, in combination with a flexible, biocompatible membrane to retain the PRP gel composition within the bone defect.
The use of an injectable PRP gel composition in combination with a suitable membrane allows easy and rapid application without the need of extensive manipulation. In addition, the use of autologous material supplementing the PRP gel composition (and/or the membrane) reduces or eliminates adverse effects caused by foreign material. The injectable PRP gel composition may typically be scaffold free, however a skilled person will know that it may be supplemented with a biodegradable support structure depending on the nature and location of the bone defect, i.e. if additional stabilization is desired.
Thus the novel biocompatible implant shows great flexibility and allows the induction and promotion of bone growth within any kind and any size of bone defect.